Antiparasitic Effect of Stilbene and Terphenyl Compounds against <i>Trypanosoma cruzi</i> Parasites

Background: Chagas disease, also known as American trypanosomiasis, is a potentially life-threatening illness caused by the protozoan parasite <i>Trypanosoma cruzi</i>. No progress in the treatment of this pathology has been made since Nifurtimox was introduced more than fifty years ago,...

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Autores principales:	Federica Bruno, Germano Castelli, Fabrizio Vitale, Simone Catanzaro, Valeria Vitale Badaco, Marinella Roberti, Claudia Colomba, Antonio Cascio, Manlio Tolomeo
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	<i>Trypanosoma cruzi</i> stilbene ST18 terphenyl TR4 Medicine R Pharmacy and materia medica RS1-441
Acceso en línea:	https://doaj.org/article/f109cc353b264baeb1e25cb6954298ae
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spelling	oai:doaj.org-article:f109cc353b264baeb1e25cb6954298ae2021-11-25T18:40:09ZAntiparasitic Effect of Stilbene and Terphenyl Compounds against <i>Trypanosoma cruzi</i> Parasites10.3390/ph141111991424-8247https://doaj.org/article/f109cc353b264baeb1e25cb6954298ae2021-11-01T00:00:00Zhttps://www.mdpi.com/1424-8247/14/11/1199https://doaj.org/toc/1424-8247Background: Chagas disease, also known as American trypanosomiasis, is a potentially life-threatening illness caused by the protozoan parasite <i>Trypanosoma cruzi</i>. No progress in the treatment of this pathology has been made since Nifurtimox was introduced more than fifty years ago, and this drug is considered very aggressive and may cause several adverse effects. This drug currently has severe limitations, including a high frequency of undesirable side effects and limited efficacy and availability, so research to discover new drugs for the treatment of Chagas disease is imperative. Many drugs available on the market are natural products as found in nature or compounds designed based on the structure and activity of these natural products. Methods: This study evaluated the in vitro antiparasitic activity of a series of previously synthesized stilbene and terphenyl compounds in <i>T. cruzi</i> epimastigotes and intracellular amastigotes. The action of the most selective compounds was investigated by flow cytometric analysis to evaluate the mechanism of cell death. The ability to induce apoptosis or caspase-1 inflammasomes was assayed in macrophages infected with <i>T. cruzi</i> after treatment, comparing it with that of Nifurtimox. Results: The stilbene ST18 was the most potent compound of the series. It was slightly less active than Nifurtimox in epimastigotes but most active in intracellular amastigotes. Compared to Nifurtimox, it was markedly less cytotoxic when tested in vitro on normal cells. ST18 was able to induce a marked increase in parasites positive for Annexin V and monodansylcadaverine. Moreover, ST18 induced the activation, in infected macrophages, of caspase-1, a conserved enzyme that plays a major role in controlling parasitemia, host survival and the onset of the adaptive immune response in Trypanosoma infection. Conclusions: The antiparasitic activity of ST18 together with its ability to activate caspase-1 in infected macrophages and its low toxicity toward normal cells makes this compound interesting for further clinical investigation.Federica BrunoGermano CastelliFabrizio VitaleSimone CatanzaroValeria Vitale BadacoMarinella RobertiClaudia ColombaAntonio CascioManlio TolomeoMDPI AGarticle<i>Trypanosoma cruzi</i>stilbene ST18terphenyl TR4MedicineRPharmacy and materia medicaRS1-441ENPharmaceuticals, Vol 14, Iss 1199, p 1199 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	<i>Trypanosoma cruzi</i> stilbene ST18 terphenyl TR4 Medicine R Pharmacy and materia medica RS1-441
spellingShingle	<i>Trypanosoma cruzi</i> stilbene ST18 terphenyl TR4 Medicine R Pharmacy and materia medica RS1-441 Federica Bruno Germano Castelli Fabrizio Vitale Simone Catanzaro Valeria Vitale Badaco Marinella Roberti Claudia Colomba Antonio Cascio Manlio Tolomeo Antiparasitic Effect of Stilbene and Terphenyl Compounds against <i>Trypanosoma cruzi</i> Parasites
description	Background: Chagas disease, also known as American trypanosomiasis, is a potentially life-threatening illness caused by the protozoan parasite <i>Trypanosoma cruzi</i>. No progress in the treatment of this pathology has been made since Nifurtimox was introduced more than fifty years ago, and this drug is considered very aggressive and may cause several adverse effects. This drug currently has severe limitations, including a high frequency of undesirable side effects and limited efficacy and availability, so research to discover new drugs for the treatment of Chagas disease is imperative. Many drugs available on the market are natural products as found in nature or compounds designed based on the structure and activity of these natural products. Methods: This study evaluated the in vitro antiparasitic activity of a series of previously synthesized stilbene and terphenyl compounds in <i>T. cruzi</i> epimastigotes and intracellular amastigotes. The action of the most selective compounds was investigated by flow cytometric analysis to evaluate the mechanism of cell death. The ability to induce apoptosis or caspase-1 inflammasomes was assayed in macrophages infected with <i>T. cruzi</i> after treatment, comparing it with that of Nifurtimox. Results: The stilbene ST18 was the most potent compound of the series. It was slightly less active than Nifurtimox in epimastigotes but most active in intracellular amastigotes. Compared to Nifurtimox, it was markedly less cytotoxic when tested in vitro on normal cells. ST18 was able to induce a marked increase in parasites positive for Annexin V and monodansylcadaverine. Moreover, ST18 induced the activation, in infected macrophages, of caspase-1, a conserved enzyme that plays a major role in controlling parasitemia, host survival and the onset of the adaptive immune response in Trypanosoma infection. Conclusions: The antiparasitic activity of ST18 together with its ability to activate caspase-1 in infected macrophages and its low toxicity toward normal cells makes this compound interesting for further clinical investigation.
format	article
author	Federica Bruno Germano Castelli Fabrizio Vitale Simone Catanzaro Valeria Vitale Badaco Marinella Roberti Claudia Colomba Antonio Cascio Manlio Tolomeo
author_facet	Federica Bruno Germano Castelli Fabrizio Vitale Simone Catanzaro Valeria Vitale Badaco Marinella Roberti Claudia Colomba Antonio Cascio Manlio Tolomeo
author_sort	Federica Bruno
title	Antiparasitic Effect of Stilbene and Terphenyl Compounds against <i>Trypanosoma cruzi</i> Parasites
title_short	Antiparasitic Effect of Stilbene and Terphenyl Compounds against <i>Trypanosoma cruzi</i> Parasites
title_full	Antiparasitic Effect of Stilbene and Terphenyl Compounds against <i>Trypanosoma cruzi</i> Parasites
title_fullStr	Antiparasitic Effect of Stilbene and Terphenyl Compounds against <i>Trypanosoma cruzi</i> Parasites
title_full_unstemmed	Antiparasitic Effect of Stilbene and Terphenyl Compounds against <i>Trypanosoma cruzi</i> Parasites
title_sort	antiparasitic effect of stilbene and terphenyl compounds against <i>trypanosoma cruzi</i> parasites
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/f109cc353b264baeb1e25cb6954298ae
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Antiparasitic Effect of Stilbene and Terphenyl Compounds against <i>Trypanosoma cruzi</i> Parasites

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